| Hypoxia potentiates microRNA-mediated gene silencing through posttranslational modification of Argonaute2. | |
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MedLine Citation:
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PMID: 21969601 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypoxia contributes to the pathogenesis of various human diseases, including pulmonary artery hypertension (PAH), stroke, myocardial or cerebral infarction, and cancer. For example, acute hypoxia causes selective pulmonary artery (PA) constriction and elevation of pulmonary artery pressure. Chronic hypoxia induces structural and functional changes to the pulmonary vasculature, which resembles the phenotype of human PAH and is commonly used as an animal model of this disease. The mechanisms that lead to hypoxia-induced phenotypic changes have not been fully elucidated. Here, we show that hypoxia increases type I collagen prolyl-4-hydroxylase [C-P4H(I)], which leads to prolyl-hydroxylation and accumulation of Argonaute2 (Ago2), a critical component of the RNA-induced silencing complex (RISC). Hydroxylation of Ago2 is required for the association of Ago2 with heat shock protein 90 (Hsp90), which is necessary for the loading of microRNAs (miRNAs) into the RISC, and translocation to stress granules (SGs). We demonstrate that hydroxylation of Ago2 increases the level of miRNAs and increases the endonuclease activity of Ago2. In summary, this study identifies hypoxia as a mediator of the miRNA-dependent gene silencing pathway through posttranslational modification of Ago2, which might be responsible for cell survival or pathological responses under low oxygen stress. |
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Authors:
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Connie Wu; Jessica So; Brandi N Davis-Dusenbery; Hank H Qi; Donald B Bloch; Yang Shi; Giorgio Lagna; Akiko Hata |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-10-03 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 31 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-11-09 Completed Date: 2011-12-30 Revised Date: 2012-03-09 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 4760-74 Citation Subset: IM |
Affiliation:
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Graduate Program in Biochemistry, Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts 02111, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Argonaute Proteins / genetics, metabolism* Cell Hypoxia / genetics Cells, Cultured Cytoplasmic Granules / metabolism Eukaryotic Initiation Factors / genetics, metabolism Gene Expression Gene Expression Regulation Genes, Reporter Green Fluorescent Proteins / biosynthesis, genetics HSP90 Heat-Shock Proteins / metabolism Humans Hydroxylation Lung / cytology, metabolism Male MicroRNAs / genetics, metabolism* Muscle, Smooth, Vascular / cytology Myocytes, Smooth Muscle / metabolism Primary Cell Culture Procollagen-Proline Dioxygenase / genetics, metabolism Protein Processing, Post-Translational* Protein Transport Pulmonary Artery / cytology RNA Interference* Rats Ribonuclease III / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HL093154/HL/NHLBI NIH HHS; R01 HL093154-05/HL/NHLBI NIH HHS; R01 HL108317-08/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Argonaute Proteins; 0/EIF2C1 protein, human; 0/EIF2C2 protein, human; 0/EIF2C3 protein, human; 0/EIF2C4 protein, human; 0/Eukaryotic Initiation Factors; 0/HSP90 Heat-Shock Proteins; 0/MicroRNAs; 147336-22-9/Green Fluorescent Proteins; EC 1.14.11.2/Procollagen-Proline Dioxygenase; EC 3.1.26.3/DROSHA protein, human; EC 3.1.26.3/Ribonuclease III |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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